Inhibitory Peptides targeting FAS-apoptotic pathways for the treatment of ischemia-reperfusion injuries – PepFAS
New therapeutic strategy for the treatment of acute myocardial infarction
Beside reperfusion of the culprit artery, no treatment is available for reperfusion injury. Our strategy is based on the administration of peptides inhibiting apoptosis induced by the re-opening of the artery, which allows the reduction of infarct size.
Inhibiting cell death during myocardial ischemia-reperfusion injury
The invention concerns the development of a therapeutic tool to treat acute myocardial infarction, a leading cause of world-wide cardioavascular mortality. Beside reperfusion by thrombolysis or angioplasty, which is nowadays the only recommended treatment, there is no efficient therapeutics for reperfusion injury. Our strategy is based on the administration of peptides able to specifically block the downstream cascade of the Death-receptor FAS, specifically activated during the acute phase of infarction. In this maturation project, our objective will be to study the cardioprotective mechanisms as well as the cellular trafficking of these peptides, both in vitro and in vivo. The second objective will be the validation of the therapeutic potential of our peptide in a large animal model closer to human physiology.
Experiments in isolated adult cells will be conducted in murine cardiomyocytes in order to determine mechanisms of cellular translocation. In vivo experiments will be realized in a murine myocardial ischemia-reperfusion model to demonstrate the therapeutic potential of these peptides. Long-term cardioprotection will be evaluated during the post-infarction period and a large animal model (pig) will be used to validate the therapeutic strategy in terms of a clinical translation. In fine, this project should provide an anti-apoptotic therapeutic tool ready to use for preclinical safety studies.
Our study in a murine model of myocardial ischemia-reperfusion shows a reduction both in infarct size (59,5 %) and apoptosis (60%). This treatment will be devoted to all patients suffering of acute myocardial infarction, independtly of the re-opening artery method, angioplasty versus thrombolysis. A partnership with a big pharma should allows us to develop a pharmacological molecule easy to use and ready for pre-clinical testing.
The stage of development consisting seeking industrial partners and investors has been completed. A research contract with a pharmaceutical industry is being signed. Contacts have been established with investors for joint development (Investment Fund SATT, Eramondi).
An international Patent PCT/EP2011/070404 was published on May 24, 2012. The national validation phases took place on 23/05/2013 in all the world. A pharmaceutical company has an option to license to be raised according to the results obtained in the framework of a collaboration.
Myocardial infarction is a leading cause of morbidity and mortality worldwide and infarct size is a major determinant of myocardial functional recovery and mortality after acute myocardial infarction (AMI). Reperfusion is the most effective treatment to reduce infarct size resulting from myocardial ischemia but, despite obvious benefits, it also has deleterious effects called ischemia-reperfusion (IR) injury including cardiomyocyte cell death. Recent progresses in our understanding of the endogenous mechanisms of apoptotic cell death mechanisms have allowed us to propose a new strategy for AMI treatment whose development and certification is the object of this grant application. In a previous work using DAXX dominant negative (DAXX-DN) transgenic mice, the FAS:DAXX (DAXX: death-associated protein) pathway was identified as a major contributor in IR injuries (Roubille et al., 2007). FADD (Fas associated protein with dead domain) is another main adaptor protein of the death-receptor FAS and its role in apoptosis, survival, growth/proliferation, cell cycle progression and inflammation has been described in various tissues and cell types.
Targeting apoptotic cascades has turned difficult with small drugs since proteins generally interact over large surfaces lacking well-defined pockets. Biomolecules such as peptides are often more selective to their target as low molecular weight conventional drugs and they can be tailored for optimal affinity or metabolic stability. Since peptides do not cross freely biological membranes, they are generally administered in association with vectors (CPPs), which in turn can be engineered for selective organs or tissues targeting. As a first approach in vivo, we made use of the already known BH4 peptidic inhibitor of the mitochondrial apoptotic pathway, which showed cardioprotective properties in a murine model of AMI after a single bolus of intravenous administration (Boisguerin et al., 2011, with journal’s issue editorial and cover page).
We used the SPOT technique to select specific inhibitor peptides for FAS:DAXX and FAS:FADD interactions that were the object of an international patent deposit filed by the CNRS together with FIST S.A. (PCT/EP2011/070404). A single systemic administration at low doses at the onset of reperfusion leads to cardioprotection in a murine model of AMI, thus providing a promising non invasive peptidic strategy to prevent reperfusion injuries.
Therapeutic peptides represent particularly well-suited drugs case since the anti-apoptotic agent only needs to be present over a short time-window and should preferably be rapidly eliminated to minimize side effects (toxicity or immunogenicity). Importantly, similar strategies and tools are likely to be adaptable to many other situations in which cells have to be protected from apoptosis such as stroke, diabetes or organ transplantation. Our consortium associates cell biologists, chemists, physiologists and clinicians with a long experience in translational research.
In this maturation phase project, our combined expertise will be used to gain more insights into the mechanism of cardioprotection, to study the traffic of these peptides in vitro and in vivo, to optimize their anti-apoptotic properties, to target them to the cardiac tissue (with delivery vectors), and to investigate their long term effects on heart functionality as well as their applications for the treatment of other pathologies involving apoptosis, as steps towards clinical development. Final products will be well-characterized peptidic anti-apoptotic drugs ready for preclinical safety studies. Based on our patent (and potential new ones) we are looking for industrial partners (licensing) to develop clinically applicable drugs. In parallel, we are also considering the possibility to create our own spin-off start-up with the help of Montpellier Agglomération BIC.
Madame Stéphanie BARRERE-LEMAIRE (Institut de Génomique Fonctionnelle - Equipe Cardioprotection: aspects physiologiques et génétiques.) – firstname.lastname@example.org
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
FIST France Innovation Scientifique et Transfert
CRBM centre de recherche de biochimie macromoléculaire
IGF Institut de Génomique Fonctionnelle - Equipe Cardioprotection: aspects physiologiques et génétiques.
Help of the ANR 270,481 euros
Beginning and duration of the scientific project: September 2012 - 24 Months